The hematological world was entranced when in 1999 imatanib (Gleevec in America, Glivec in the rest of the world; pronounced the same however it is spelled) was shown in a phase 1 dose finding study to introduce molecular remissions in chronic myeloid leukemia. Imatanib is an orally active tyrosine kinase inhibitor. There are about 1800 different kinases in the human cell, and the hunt was on for other inhibitors that would work in other forms of cancer.
So far the kinase inhibitors that have been tested have not been as good as Glivec - no, that's not true, there are better inhibitors than Glivec, there hasn't been such a good target as bcr/abl in other cancers.
CAL 101 is a small molecule inhibitor of the delta isoform of the 110 kDa catalytic subunit of class IA phosphoinositide-3 kinases (PI3K) with potential immunomodulating and antineoplastic activities. It inhibits the production of the second messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3), preventing the activation of the PI3K signaling pathway.
This pathway is illustrated to the left of this schematic diagram, which shows some of the ways that a stimulus to the surface of a cell is transmitted to the nucleus where transcription factors are activated. Trancription factors are responsible for the reading of DNA and the subsequent enactment of its message in the cell. Unlike other isoforms of PI3K, PI3K-delta is expressed primarily in hematopoietic lineages. Thus it could be seen as targeted towards leukemias and lymphomas, though it would also suggest that suppression of normal hematopoiesis might be a side effect.
An interim report of a phase 1 clinical trial of CAL-101 in patients with relapsed or refractory CLL, indolent non-Hodgkin’s lymphoma (NHL), aggressive NHL, acute myeloid leukemia (AML), and multiple myeloma (MM) was given at last year's IWCLL meeting in Barcelona. At this interim assessment, 29 percent of CLL patients treated at the dose level at which it was decided to expand the cohort had partial responses observed after 28 days of therapy (1 cycle) and 94 percent achieved evidence of biologic activity with a greater than 50 percent shrinkage of lymph node tumors. Five out of six partial responders continue treatment with CAL-101, with the longest response greater than 224 days. All patients had prior rituximab and fludarabine therapy and nearly half of the patients had prior alemtuzamab therapy. Half of the patients were refractory to their last therapy prior to entering the study. A low incidence of hematologic toxicity was observed. The dose limiting toxicity in the study was an elevation of transaminases (ALT and AST), which has been both monitorable and reversible and patients were usually able to resume therapy at a lower dose.
Last month a new trial with Ian Flinn as Principle investigator was begun in CLL. This will be a Phase I Study to Investigate the Safety and Clinical Activity of CAL-101 in Combination With Bendamustine and Rituximab in Patients With Relapsed or Refractory Indolent B-cell Non-Hodgkin's Lymphoma or Chronic Lymphocytic Leukemia. The Primary Outcome Measures will be Safety of CAL-101 in combination with rituximab and bendamustine - assessed by adverse events, vital signs, clinical laboratory tests and ECG. The Secondary Outcome Measures will be clinical activity evaluated by clinical response rate - assessed by CT scan, clinical laboratory tests and bone marrow biopsy if indicated; plasma concentrations of CAL-101; plasma concentrations of bendamustine in a select subset of patients; and the pharmacodynamic effects of CAL-101 treatment - assessed by comparing pre and post dose blood samples.
There will be three arms to the study: CAL-101 daily for 12 28-day cycles plus treatment with rituximab for 8 weekly doses over the first 2 cycles (CAL-101 100 mg by mouth twice daily; Rituximab 375 mg/m2 administered intravenously); CAL-101 daily for 12 28-day cycles plus bendamustine on days 1 & 2 of Cycles 1-6 (CAL-101 100 mg by mouth twice daily; Bendamustine 90 mg/m2 administered intravenously); and CAL-101 daily for 12 28-day cycles plus rituximab on day 1 and bendamustine on days 1 & 2 of Cycles 1-6 (CAL-101 100 mg by mouth twice daily; Rituximab 375 mg/m2 administered intravenously; Bendamustine 90 mg/m2 administered intravenously). Inclusion criteria are patients with CLL or indolent lymphoma, previously treated with relapsed or refractory disease (refractory defined as not responding to a standard regimen or progressing within 6 month of the last course of a standard regimen)
and WHO performance status of ≤ 2. Exclusion criteria: Not a good candidate according to the clinical judgment of the investigator; Patients with atypical immunophenotype with t(11:14) translocation or cyclin D1 over-expression; Had radiotherapy, radioimmunotherapy, biological therapy, chemotherapy, or treatment with an investigational product within 4-weeks prior to the baseline disease status tests; Had treatment with a short course of corticosteroids for symptom relief within 1-week prior to the baseline tests; Has had an allogeneic hematopoietic stem cell transplant; Has known active central nervous system involvement of the malignancy; Is pregnant or nursing; Has active, serious infection requiring systemic therapy; Has a positive test for human immunodeficiency virus (HIV) antibodies; Has active hepatitis B or C. Patients with serologic evidence of prior exposure are eligible.
Four centers are registered: Nashvill, NCI, Cornell and St Louis. Details can be found here.
This may not be Glivec but it looks a worthwhile and encouraging agent acting in a way different to anything else that has been tried in CLL.